(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile (formula I) has been reported as inhibitor of DPP-IV. As a result, it is useful in the treatment of disorders mediated by DPP-IV such as, but not limited to, diabetes, type II diabetes, hyperglycemia, Syndrome X, hyperinsulinemia and obesity.
The synthetic route that was used to prepare the trifluoroacetic acid salt of (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile as disclosed in U.S. Patent Application Publication Number US2004/0121964, is outlined in Scheme 1 below. Specifically, the synthesis includes reaction of an acid of formula (II) with triphenyl phosphine and diphenylphosphoryl azide provided carbamate of formula (III), which was treated with HCl in dioxane to provide amine of formula (IV). A refluxed solution of 2-fluoroisonicotic acid (formula (V)) in benzene and 2-methyl-propan-2-ol was treated with N,N-dimethylformamide di-tert-butyl acetal to provide a protected acid of formula (VI). Displacement of the fluorine atom of formula (VI) with amine of formula (IV) occurred, followed by treatment with ammonium formate in the presence of 10% palladium on carbon at elevated temperature provided amine of formula (VIII). Treatment of methyl (S)-(+)-2-pyrrolidone-5-carboxylate with methyl chloroformate in the presence of lithium bis(trimethylsilyl)amide provided the corresponding methyl carbamate of formula (IX). Reduction of the compound of formula (IX) with lithium triethylborohydride occurred, followed by treatment with methanol in the presence of p-toluenesulfonic acid hydrate provided ether of formula (X). Treatment of the ether with bistrimethylsilylacetylene, tin(IV) chloride and aluminum chloride was followed by separation of the diastereomers using column chromatography gave the desired diastereomer of formula (XI). Treatment of compound of formula (XI) with iodotrimethylsilane afforded the deprotected L-pyrolidnate of formula (XII). Reaction of compound of formula (XII) with chloroacetyl chloride provided 1-chloroacetyl-L-prolinate of formula (XIII). Hydrolysis of the compound of formula (XIII) with lithium hydroxide provided an acid of formula (XIV). Acid of formula (XIV) was treated with isobutyl chloroformate in the presence of 4-methylmorpholine, and the resulting intermediate was treated with a solution of ammonia in dioxane to provide amide of formula (XV). Dehydration of amide of formula (XV) with phosphoryl chloride in the presence of imidazole and pyridine provided the compound of formula (XVI). Displacement of the chloride of formula (XVI) with the amine of formula (VIII) was followed by purification using column chromatography provided compound of formula (XVII). Treatment of compound of formula (XVII) with trifluoroacetic acid in dichloromethane produced the trifluoroacetic acid salt of compound of formula (I).

The above procedure entails formation of two diastereomeric intermediates (XI) and (XIa) and the requirement of chromatographic purification to obtain the desired diastereomer (XI). In addition, displacement of the chloride of formula (XVI) with amine of formula (VIII) was conducted in an aqueous dioxane environment at room temperature. Combination of these two operations resulted in low overall yield of the process. Therefore, the synthetic method outlined above is not suitable for large-scale preparation of the compound of formula (I) or salts thereof.